G-protein coupled receptors (GPCRs) are encoded by the largest superfamily of genes in the mammalian genome (Marinissen and Gutkind, Trends Pharmacol Sci 22:368-376, 2001). GPCRs play an integral part in regulating physiological functions such as neurotransmission, and release of hormones and enzymes involved in signaling and immune responses (Dorsam and Gutkind, Nat Rev Cancer 7:79-94, 2007; Lee et al., Pigment Cell Melanoma Res 21:415-428, 2008). These receptors are activated by a variety of ligands, such as hormones and growth factors. The important role these molecules play in many human diseases is evident by the fact that 50-60% of the current FDA approved therapeutics target GPCRs or their direct downstream signaling components (Flower, Biochim Biophys Acta 1422:207-234, 1999). As GPCRs are involved in the regulation of signal transduction pathways that are central to cell growth regulation, their genetic analysis in cancer is warranted.
Melanoma is the most common form of skin cancer. Despite years of research, metastatic melanoma disease has a dismal prognosis and is often fatal (Jemal et al., CA Cancer J Clin 59:225-249, 2009). There are few therapeutic options for melanoma patients, demonstrating a need for new clinically relevant targets. Thus, a systematic genetic analysis of genes involved in signal transduction such as the GPCRs that are important for cell survival, proliferation and migration is needed in order to identify novel therapeutic targets.